AbstractWhile recent medical innovation shows great promise in treating hepatitis C (HCV), it remains a condition associated with profound stigma. HCV is a bloodborne virus (BBV) most commonly transmitted in high-income countries by injecting drug use, and it is the stigmatising association between the two which is deeply problematic for those with HCV.

A qualitative study undertaken in 2002 found that disclosure in health settings places those with HCV in positions of pronounced vulnerability. Disclosure is a primal scene, an interface, where the stigma of HCV, replete with connotations of disease and deviance, potentially transforms those affected into shamed subjects. Standard precautions protect health workers and minimise the transmission of contagion, measures which, in theory, also mitigate the requirement of those with BBVs to unnecessarily disclose their blood status.

However, questions on pre-employment health checks, concerns that health treatments might adversely affect the liver and an ethical need to pre-emptively inform healthcare professionals undertaking exposure prone procedures are occasions when those with HCV confront the decision to disclose their blood status.

This paper employs Goffman's model of actual and virtual social identities, along with Douglas' notion of dirt and pollution, to examine the dilemmas around disclosure those with HCV negotiate within the health setting. Discriminatory responses by healthcare professionals elucidate the stigmatising potential HCV carries. The subsequent reticence by those with HCV to disclose their blood status risks less than optimum healthcare. Recent studies indicate that stigma occurring in health settings remains a perennial concern for those with HCV.

Decision enables price reductions and scale-up of treatment that leads to cure in 95% of cases

Treatment for hepatitis C using the key drug sofosbuvir could be vastly scaled up in Brazil after the decision by the National Agency of Health Surveillance (Anvisa) to reject a key patent application on the drug marketed by pharmaceutical corporation Gilead. The decision could pave the way to enable generic competition in Brazil, which should lead to price reductions, making it more affordable to scale up treatment.

“In Brazil, as in many other countries, the high price charged by Gilead for sofosbuvir has meant treatment rationing. A report by WHO issued in October 2016 shows that out of 80 million people infected with hepatitis C worldwide, only 5.4 million people, including only 1 million people from low- and middle-income countries, had access to new treatment options”, said Felipe de Carvalho, Brazil Coordinator of Médecins Sans Frontières’ Access Campaign. “On the other hand, it is very encouraging to see in the report that countries achieving great results in treatment coverage are the ones where generics are available. We need a coordinated global effort to ensure effective medicines are available to the largest number of people as soon as possible – and this decision in Brazil is a step towards that.”

The exorbitant cost of sofosbuvir has prompted a global debate about inaccessible and unacceptable prices of patented drugs. In the United States, Gilead originally set the price of sofosbuvir at US$1,000 per pill – making the drug more expensive than gold – while studies show it can be produced for less than $1 per pill. This week, in Europe, MSF and partners have challenged the same patent that was rejected in Brazil by Anvisa at the European Patent Office, in order to increase access to the treatment.

In Brazil, sofosbuvir has been used in the Brazilian Public Health System (SUS) since the end of 2015. Prior to that, the Working Group on Intellectual Property (GTPI) – a collective of civil society organisations coordinated by the Brazilian Interdisciplinary Aids Association (ABIA) – had filed a patent opposition on the drug showing the patent is not merited. In the decision, Anvisa took into account GTPI’s argument that the patent application does not meet patentability criteria established in Brazilian law. Patent applications on sofosbuvir have already been rejected in Egypt, China and Ukraine.

“This decision is extremely beneficial for the 1.6 million Brazilians living with hepatitis C, because it allows the government to be more ambitious with its treatment goals. Currently, we see the violation of universal access to medicines in favour of Gilead’s abusive price”, said Pedro Villardi, GTPI coordinator. “It is important now to ensure that this decision will not be appealed and that it is validated by INPI, allowing the government to quickly buy affordable generic versions. There is an agreement under discussion that can eliminate Anvisa’s ability to reject patents based on patentability criteria. This cannot happen. If Anvisa’s decision on sofosbuvir is respected, we could potentially now treat seven times the number of people currently on hepatitis C treatment without spending more money, if Brazil buys generic sofosbuvir at the lowest global prices.”

Gilead currently charges $6,293 for a 12-week treatment course of sofosbuvir in Brazil. The best generic prices are currently available for around $200 per treatment course, but access is restricted by voluntary licences signed by Gilead, which block sales to countries like Brazil. In June 2016, an initiative for local production of a generic version of sofosbuvir was announced by a consortium that announced a price less than half of what Gilead charges. In early 2017, this consortium also filled a patent opposition. Following the patent rejection, generic versions could soon enter the market, reducing the price and expanding access to treatment.

“Brazil is a high-burden country for hepatitis C and so far, around 30,000 people have received new treatments – it’s crucial we scale up treatment with affordable versions of sofosbuvir. In some States, even people in an advanced stage of the disease have had to wait a long time to get treatment”, said Arair Azambuja, president of the Brazilian Movement of Viral Hepatitis (MBHV). “We are talking about a cure that is cheap to produce; it should not be priced out of reach. We hope Brazilian stakeholders make efforts to bring prices to the lowest levels, so we can really tackle the hepatitis C epidemic in Brazil.”

With the help of an expert panel of independent doctors and dietary-supplement researchers, Consumer Reports identified 15 supplement ingredients that are potentially harmful. The risks include organ damage, cancer, and cardiac arrest. The severity of these threats often depends on such factors as pre-existing medical conditions as well as the quantity of the ingredient taken and the length of time a person has been exposed to the substance.

Many of the ingredients on this list also have the potential to interact with prescription and over-the-counter medications, such as cholesterol-lowering statins and blood-thinning drugs like aspirin and warfarin (Coumadin and generic).

Moreover, our experts agree that none of these supplement ingredients provide sufficient health benefits to justify the risk. Even so, we found all 15 ingredients in products available online or in major stores such as GNC, Costco, CVS, Walmart, and Whole Foods. (Download this PDF to find out more about how we selected these ingredients, our panel of dietary supplement experts, and how we shopped for products.)Continue reading....

Many green tea supplements on the market claim to help with weight loss or a healthier metabolism, but health experts at Consumer Reports warn the products could actually be dangerous and recommend you avoid them altogether.

“Higher concentrations of green tea extract can potentially cause serious liver damage. Plus the herb itself has been found to alter the effectiveness of a long list of drugs, including certain antidepressants and anti-clotting medications,” said Jeneen Interlandi, Consumer Reports.Continue reading....

Although the liver is the primary target for hepatitis C virus (HCV) infection, it is well established that many other organ systems are affected, increasing the overall burden of disease [1, 2, 3]. In a recent article, Nuño Solinís and co-authors assessed the overall disease burden of chronic HCV across 354 clinical studies in over 500,000 patients, including the impact of early versus late treatment [4]. Their article included some valuable insights into the contributions that extrahepatic manifestations (EHMs) make towards the overall morbidity and mortality of the disease. The authors concluded that early treatment leads to a strong and consistent reduction in the burden of chronic hepatitis C infection, from both clinical and economic perspectives. The economic argument for early treatment has been addressed by Nuño Solinís and colleagues [4]. in this response, I highlight the burden of HCV EHMs and present an ethical argument for treating HCV early to minimize both the individual and collective burdens of HCV-related diseases.

In the face of insurmountable evidence for the benefit of treating patients early, a concerted effort is required to alter the actions of governments and policymakers to realize real-world changes in clinical practice. As the current infected population ages, the burden of decompensated cirrhosis and hepatocellular carcinoma is set to rise until at least 2030, and potentially beyond this in countries such as Russia, where the number of new infections continues to increase [5]. In a series of publications that modeled the future burden of HCV in 47 countries [5, 6, 7], the authors found rare exceptions such as the Netherlands, where the future burden of HCV is predicted to decrease because the country has a high treatment rate using newer therapies with high viral cure rates [5].

Although the majority of governments provide limited access to newer and highly effective direct-acting antivirals (DAAs), Nuño Solinís and colleagues highlight examples of government programs designed to widen access to diagnosis and treatment of HCV infection [4]. These countries include Georgia, Mongolia, Egypt, Australia, and France, and the outcomes of these programs should be closely monitored to inform other countries’ health policy and effect real-world changes to eliminate HCV infection and reduce future HCV-related disease burden.

High cost of Extrahepatic Disease

EHMs such as neuropsychiatric conditions, glomerulonephritis, and insulin resistance can increase morbidity and mortality at all stages of liver disease, not only when liver disease is advanced [3]. The implications of extrahepatic disease have far-reaching consequences, both individual and societal. Studies have shown a substantial negative effect of HCV on health-related quality of life, including general health and social functioning, which also impacts work productivity [8, 9]. Viral eradication was associated with improved health-related quality of life and work productivity, independent of liver fibrosis stage [9]. The economic burden of HCV EHMs is considerable: a recent meta-analysis reported that the estimated direct costs were in the order of US$1.5 billion per year [10]. The cost is a reflection of the diverse extrahepatic diseases associated with HCV and the high proportion (up to 74%) of patients with chronic HCV that are affected by these diseases. The prevailing practice is to delay treating patients with mild liver disease. However, if patients are treated earlier, treatment duration can potentially be shorter and more effective, the progression towards cirrhosis and decompensated disease is reduced, and the contribution of EHMs to all-cause morbidity and mortality is diminished. Indeed, Nuño Solinís et al. illustrate that a significant mortality benefit is gained in patients who achieve SVR, at all stages of fibrosis [4]. The practice of delaying HCV therapy also raises ethical issues because it potentially allows the development of avoidable extrahepatic diseases and denies an improved quality of life after viral clearance [10]. Evidence presented by Nuño Solinís and colleagues show that delaying treatment could substantially increase morbidity, mortality, and medical costs [4]. The combined evidence from this systematic review of the literature suggests that early treatment intervention has a demonstrable impact on morbidity and mortality for patients with chronic HCV infection.

Reasons for delaying treatment are various, but a significant motivation includes the short-term economic cost of providing these drugs. The evidence base presented shows that treatment with DAAs is more cost-effective than older, interferon-based regimens; it also shows that treating patients with mild liver disease (METAVIR; F1–2 fibrosis) is more cost-effective than treating patients with more advanced liver disease (F3–4 fibrosis). Taken together, these two findings must call into question the value of delaying treatment. Interestingly, this corroborates the findings of a 2014 study by Younossi et al. [11] suggesting that the most cost-effective strategy is to treat patients without staging liver disease at all. Delaying treatment also ignores the considerable cost of treating and caring for patients with decompensated liver disease and hepatocellular carcinoma.

International HCV treatment guidelines acknowledge a priority for treating patients with EHMs owing to the clinical impact of extrahepatic disease and the subsequent benefits of treatment [12, 13].

This is a great step forward in reducing the long-term morbidity and mortality of HCV, but it is arguable that the best way to mitigate the impact of extrahepatic diseases is to treat early, before these complications are given a chance to arise, an approach that the current evidence base would suggest is both clinically validated and cost-effective.

Ehms and Screening
If the ultimate goal is to eradicate HCV, then a greater effort is required to screen and treat patients with HCV infection and prevent ongoing transmission. In the US alone, up to 75% of people infected with HCV are unaware of their infection [14]. The majority of patients are diagnosed incidentally during evaluation of liver transaminases or of at-risk populations such as people who inject drugs [15]. Furthermore, the majority of screening programs restrict coverage to known high-risk groups, e.g. injection drug users and prisoners [16]. An additional benefit—beyond reducing long-term costs—for an increased recognition of HCV EHMs could be an expansion of the population of patients screened for HCV. This is in part supported by international guidelines stating that patients should be prioritized for treatment if they have EHMs of HCV infection [12]. An international group of experts [the International Study Group of Extrahepatic Manifestations Related to Hepatitis C Virus (ISG-EHCV)] recently published an expert consensus statement highlighting the need for a multidisciplinary assessment of patients with HCV infection to better diagnose EHMs [2]. Those EHMs with a strong or significant association with HCV based on epidemiological, clinical, and laboratory evidence include mixed cryoglobulinemia, diabetes, and cardiovascular disease. A meta-analysis of 102 published studies found that diabetes and depression were diagnosed in 15% and 25% of patients, respectively [10]. These disorders could be included alongside other high-risk groups or combined with other negative predictors to improve HCV screening [2].

Cost-Effectiveness in the DAA Era
DAA regimens have been shown to be more cost-effective partly owing to the superior efficacy and safety profiles compared with those of interferon-containing regimens. However, the majority of the studies reviewed by Nuño Solinís and colleagues were of interferon-containing regimens and so there is still a need for a systematic review of the cost-effectiveness of DAAs. Regardless of current strategies towards HCV treatment, the cost to healthcare systems is set to rise in the near future as we enter an era in which patients who have long-standing HCV infection will require greater access to care. This is evidenced by new data showing that HCV is an independent risk factor for increased mortality and resource utilization in the baby-boomer cohort (adults born in 1945–1965) [17]. For this well-defined group, who are five times more likely to have chronic HCV [18], there is a strong argument for widespread screening of baby boomers and treating all those with chronic HCV in order to substantially reduce the future impact of hepatic and extrahepatic disease. In the US, the Center for Disease Control has issued recommendations that all baby boomers should be given a one-time HCV test [18]. Although there has been mixed success in delivering this recommendation, with low uptake in primary-care settings, the use of electronic notification systems in a variety of medical settings has resulted in substantial increases in the number of people screened [19, 20]. A recent study in the US showed that investments in HCV screening and treatment are expected to “break even” from a social perspective after only 8–9 years when treatment is expanded to include stages F0–F2, compared with 20–22 years when treatment is limited to fibrosis stages F3–F4 [21].

Summary
As demonstrated in the review by Nuño Solinís et al. [4], we now have highly effective, well-tolerated, and cost-effective therapies to treat essentially anyone who is infected with HCV. With these tools, we can prevent not only hepatic but also many extrahepatic diseases caused by HCV. As such, I believe that interferon-free DAA therapy should be offered to most patients that have HCV EHMs as well as to all patients at risk of developing them. This stands out as the best approach to deal with the serious complications of chronic HCV infection and to speed the way to a world in which HCV is effectively eradicated.

For hepatitis C patients who receive liver transplants, a population that is challenging to treat with interferon-based therapy, treatment with new direct-acting antivirals (DAAs) leads to high cure rates.

The choice of which DAA to use depends on the hepatitis C virus (HCV) genotype and the severity of liver damage. Outcomes are better in people who have not yet developed severe damage in the new liver, suggesting that post-transplant treatment should be started sooner rather than later.Continue reading....

PHILADELPHIA – The road to absolute cure of hepatitis B virus (HBV) is so well understood that the strategies now being actively pursued may conceivably eliminate this infection from the human population, according to a summary of progress presented at Digestive Diseases: New Advances.

“As in HIV and hepatitis C infections, combination therapies of drugs with different mechanisms of action will be the solution. Which combination will deliver the ultimate cure is yet to be determined, but within 5 years we should have a cure,” reported Vinod K. Rustgi, MD, chief of hepatology at Robert Wood Johnson Medical School, New Brunswick, N.J.

Conference CoverageDoubt expressed about potential of any single regimen to treat all hep C
Publish date: March 30, 2017
By: Ted Bosworth Family Practice News

PHILADELPHIA – Despite combination therapies for hepatitis C virus (HCV) that are now showing high rates of sustained viral remission (SVR) across all genotypes, a one-size-fits-all treatment will not be practical in the near future, according to a review of current and coming HCV therapies at Digestive Diseases: New Advances meeting held by Rutgers, the State University of New Jersey, and Global Academy for Medical Education. Global Academy and this news organization are owned by the same company.

The presence of cirrhosis in some patients demonstrates the need for this care, for example. Many of the most effective single-pill DAA combinations are demonstrating high SVR rates for HCV patients with cirrhosis, but Dr. Brown said that identification of cirrhosis prior to HCV treatment “remains imperative.” Some pangenotypic therapies require a longer duration of treatment when cirrhosis is present, and patients with cirrhosis require posttreatment monitoring for decompensation and hepatocellular carcinoma (HCC). Patients who have failed a prior anti-HCV regimen or who are in renal failure also require more individualized care.

Wednesday, March 29, 2017

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American Academy of NeurologyViral hepatitis and Parkinson disease A national record-linkage study
We report strong evidence in favor of an elevation of rates of subsequent PD in patients with hepatitis B and hepatitis C. These findings may be explained by factors peculiar to viral hepatitis, but whether it reflects consequences of infection, shared disease mechanisms, or the result of antiviral treatment remains to be elucidated. Further work is needed to confirm this association and to investigate pathophysiologic pathways, potentially advancing etiologic understanding of PD more broadly
Study - Download PDF
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March 29, 2017
Patients with hepatitis B or hepatitis C may have a significantly increased risk for Parkinson's disease (PD), a new study suggests.
Previous research had tied hepatitis C, but not hepatitis B, to PD. Results of the new study showed no such relationship with PD among patients with autoimmune hepatitis, chronic active hepatitis, or HIV.

"Clinicians caring for patients with a history of hepatitis B or C should be aware of this seeming increased risk of PD among their patients, so that if neurological symptoms present, these are detected early," lead author, Julia Pakpoor, BA, BM, Bch, Unit of Health Care Epidemiology, Nuffield Department of Population Health, University of Oxford, United Kingdom, told Medscape Medical News.Continue reading...Hepatitis B and C may be linked to increased risk of Parkinson's disease
American Academy of Neurology

MINNEAPOLIS - The viruses hepatitis B and C may both be associated with an increased risk of Parkinson's disease, according to a study published in the March 29, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. The hepatitis virus affects the liver.

According to the Centers for Disease Control and Prevention (CDC), it is estimated that anywhere from 850,000 to 2.2 million people in the United States have chronic hepatitis B virus infection and anywhere from 2.7 to 3.9 million people have chronic hepatitis C. While both can lead to serious illness, many people have few symptoms and do not realize they have the virus, especially at first.

Hepatitis B is spread through contact with blood and body fluids of an infected person, such as unprotected sex, sharing needles, getting a tattoo or piercing with unsterilized tools or sharing razors or toothbrushes with an infected person.

Hepatitis C is spread through blood-to-blood contact such as sharing needles, razors and toothbrushes and is passed on at birth by infected mothers.

"The development of Parkinson's disease is complex, with both genetic and environmental factors," said study author Julia Pakpoor, BM, BCh, of the University of Oxford in the United Kingdom. "It's possible that the hepatitis virus itself or perhaps the treatment for the infection could play a role in triggering Parkinson's disease or it's possible that people who are susceptible to hepatitis infections are also more susceptible to Parkinson's disease. We hope that identifying this relationship may help us to better understand how Parkinson's disease develops."

For the study, researchers examined hospital records from a large British database. They looked for records of people with a first case of hepatitis B, hepatitis C, autoimmune hepatitis, chronic active hepatitis and HIV from 1999 to 2011. Then those people were compared to the hospital records of people with relatively minor conditions such as cataract surgery, bunions and knee replacement surgery. For all of the participants, researchers looked at the records to see who later developed Parkinson's disease.

There were nearly 22,000 people with hepatitis B, 48,000 with hepatitis C, 6,000 with autoimmune hepatitis, 4,000 with chronic active hepatitis and nearly 20,000 with HIV. They were compared to more than 6 million people with minor conditions.

The study found that people with hepatitis B were 76 percent more likely to develop Parkinson's disease than those in the comparison group, and people with hepatitis C were 51 percent more likely to develop Parkinson's disease. A total of 44 people with hepatitis B developed Parkinson's disease, compared to 25 cases that would be expected in the general population. For people with hepatitis C, 73 people developed Parkinson's disease, where about 49 cases would have been expected in the general population.

People with autoimmune hepatitis, chronic active hepatitis and HIV did not have an increased rate of Parkinson's disease.

A previous study from Taiwan showed a relationship between hepatitis C and Parkinson's disease, but it did not show any relationship for hepatitis B.

Pakpoor said that limitations of the current study include that they could not adjust for lifestyle factors such as smoking and alcohol use, which could affect Parkinson's disease risk, and that the study was based solely on people who were evaluated at a hospital.

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The British National Institute for Health Research funded the development of the datasets and software.

The American Academy of Neurology is the world's largest association of neurologists and neuroscience professionals, with 32,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer's disease, stroke, migraine, multiple sclerosis, concussion, Parkinson's disease and epilepsy.

AGA Institute releases practice update for managing patients cured of HCV infection
The American Gastroenterological Association (AGA) Institute released a practice update on managing patients with chronic hepatitis C virus (HCV) infection who have attained a sustained virologic response (SVR) after antiviral treatment. The clinical practice update was published in Gastroenterology.

Direct-acting antiviral (DAA) regimens for chronic HCV infection achieve high rates of SVR and have replaced interferon (IFN) in many countries. The current definition of SVR is undetectability of HCV RNA at 12 weeks after treatment (SVR12). Patients who achieve an SVR have a less than 1% risk of relapse and are considered cured.

Chronic hepatitis C virus (HCV) infection is well-recognized as a common blood borne infection with global public health impact, affecting 3 to 5 million persons in the U.S. and over 170 million persons worldwide. Chronic HCV infection is associated with significant morbidity and mortality due to complications of liver cirrhosis and hepatocellular carcinoma (HCC). Current therapies with all-oral directly acting antiviral agents (DAAs) are associated with high rates of sustained virologic response (SVR), generally exceeding 90%. SVR is associated with a reduced risk of liver cirrhosis, hepatic decompensation, need for liver transplantation, and both liver-related and all-cause mortality. However, a subset of patients who achieve SVR will remain at long-term risk for progression to cirrhosis, liver failure, HCC, and liver-related mortality. Limited evidence is available to guide clinicians on which post-SVR patients should be monitored versus discharged, how to monitor and with which tests, how frequently should monitoring occur, and for how long. In this clinical practice update, available evidence and expert opinion are used to generate best practice recommendations on the care of patients with chronic HCV who have achieved SVR.

IndexAssessment of HCV RNA after SVR12 has been attainedWith the initiation of trials of DAA regimens, initially in combination with interferon and later without it, the attainment of SVR 12 weeks after completion of treatment replaced SVR24 as the primary endpoint, defined as undetectable HCV RNA on a highly sensitive PCR assay (lower limit of detection <12 IU/mL). This transition was based upon the rarity of relapse after followup week 12, and it helped move the field ahead by shortening the intervals between successive trials in development programs (22). It has become apparent that late relapse beyond this time point is no more common, and perhaps less so, than it was after interferon-based therapyOngoing surveillance for hepatocellular carcinoma after SVRIs HCC risk after SVR exclusive to patients with advanced fibrosis and cirrhosis? Can HCC surveillance ever be discontinued? How should screening for, and management of, varices be affected by SVR? Should patients be routinely monitored for regression of advanced fibrosis or cirrhosis? Recurrent HCC After SVR Reinfection Lifestyle Measures ConclusionsContinue reading...

Full Text Articles
I highly suggest you follow Henry E. Chang on Twitter if you are interested in reading full text articles about the treatment and management of hepatitis C.A link to the above full text PDF article was tweeted today.

Scientific discovery opens new possibilities for cancer and fibrosis treatment

Researchers from the Turku Centre for Biotechnology (BTK) in Finland have discovered that a cellular fuel sensor, known to control energy processes in the cells, is involved in the regulation of the contact of cells with their surrounding environment. This unexpected link could help scientists better understand life-threatening diseases, such as cancer and tissue fibrosis.

The researchers found that a cellular fuel sensor called AMPK controls integrin function and the production of extracellular matrix.

- This is a significant finding, since the rather cheap and widely used drug called metformin activates the AMPK sensor in particular and inhibits diabetes, cancer, fibrosis and cardiovascular diseases, and promotes longevity. Our discovery opens up new therapeutic opportunities for the treatment of these diseases, says Academy Professor Johanna Ivaska, senior author of the study.

The space between the cells of human tissues is filled with a meshwork of different proteins called the extracellular matrix. The cells are connected with the extracellular matrix through protein complexes called adhesions. The main proteins in those adhesions are the integrins which link the cytoskeleton with its environment. The researchers have found that in the absence of the fuel sensor AMPK, fibroblasts activate their integrins increasing their adhesion and matrix production. This increase is attributed to a protein called tensin.

- AMPK is known to control energy homeostasis. In our study, we have shown that this fuel sensor can also regulate integrin signaling and matrix formation, suggesting that AMPK serves as a general master switch in our body. Our aim was to identify potential novel targets to treat diseases associated with excessive matrix formation, such as cancer and fibrotic diseases which are major causes of morbidity and mortality worldwide, reports Maria Georgiadou, first author of the work.

Tuesday, March 28, 2017

US could be rid of hepatitis B and C as public health problems, preventing nearly 90,000 deaths by 2030, with better attention to prevention, screening, treatment, and creative financing for medicines

National Academies of Sciences, Engineering, and Medicine

WASHINGTON - Hepatitis B and C kill more than 20,000 people every year in the United States. A new report from the National Academies of Sciences, Engineering, and Medicine presents a strategy to eliminate these diseases as serious public health problems and prevent nearly 90,000 deaths by 2030.

A National Strategy for the Elimination of Hepatitis B and C: Phase Two Report

"Viral hepatitis is simply not a sufficient priority in the United States," said Brian Strom, chair of the committee that carried out the study and chancellor and university professor, Rutgers Biomedical and Sciences, Rutgers University, Newark, N.J. "Despite being the seventh leading cause of death in the world - and killing more people every year than HIV, road traffic accidents, or diabetes - viral hepatitis accounts for less than 1 percent of the National Institutes of Health research budget."

About 1.3 million people in the United States have chronic hepatitis B, and about 2.7 million have chronic hepatitis C. These infections also increase risk of liver cancer. Together, hepatitis B and C cause about 80 percent of the cases worldwide of liver cancer, which has been steadily increasing in both new cases and deaths in the United States since the early 2000s. The incidence of liver cancer in the United States increased 38 percent between 2003 and 2012, and liver cancer deaths increased 56 percent in the same time, primarily due to viral hepatitis.

The world has the tools to prevent these deaths. Hepatitis B is preventable with vaccination, and recent advances in treatment make hepatitis C curable with short and easily tolerable courses of medicines. The committee said the number of deaths from hepatitis B could be cut in half by 2030 by diagnosing 90 percent of the nation's chronic hepatitis B patients, bringing 90 percent of those to care, and treating 80 percent of those for whom treatment is warranted. These actions would avert more than 60,000 deaths and also reduce liver cancer and cirrhosis from hepatitis B infection by about 45 percent. Similarly, treating everyone with chronic hepatitis C would reduce new infections by 90 percent by 2030 and reduce hepatitis C deaths by 65 percent over the same time. These actions would avert 28,800 deaths by 2030 and depend on diagnosing 110,000 new cases a year between now and 2020, gradually dropping off to 70,000 a year by 2025.

The committee said eliminating hepatitis B and C as public health problems in the U.S. by 2030 will require a significant departure from the status quo - including aggressive testing, diagnosis, treatment, and prevention methods, such as needle exchange. It called for a coordinated federal effort to manage hepatitis elimination, and it recommended expanding syringe exchange for people who inject drugs, free hepatitis B vaccine in pharmacies and other easily accessible places, and unrestricted treatment for everyone with hepatitis C. Because the medicines that cure chronic hepatitis C are expensive, the committee gave considerable attention to novel ways to pay for them and recommended a voluntary licensing agreement between the federal government and a patent-holding pharmaceutical company as a way to make the drug more affordable for Medicaid beneficiaries and other underserved patient populations.

Prevention is the first step to eliminating the public health problems of hepatitis B and C, the committee said. About 90 percent of U.S. children were fully immunized against hepatitis B in 2013, but only about a quarter of adults over 19 were immunized. If states supported hepatitis B vaccination to the same level as the seasonal influenza vaccine, great improvements could be made. Offering vaccination in pharmacies is one way to reach a wider cross-section of society, but some states restrict the types of vaccines offered in pharmacies and the circumstances under which pharmacists may administer them. The committee recommended that states expand access to adult hepatitis B vaccination, removing barriers for free immunization in pharmacies and other easily accessible settings.

Hepatitis B virus can easily pass from mother to baby, and the committee was concerned with preventing such cases. Children born to women with chronic hepatitis B require immunization within 12 hours of birth, and other children should receive it within a day of birth. The committee recommended that the National Council on Quality Assurance monitor the delivery of the first dose of hepatitis B vaccine, thereby drawing attention to this essential service. There are also cases where preventive measures are not enough to stop the virus from passing from a mother to her child. Expectant mothers with hepatitis B should have testing early in pregnancy to measure viral DNA, the committee said. This would identify highly viremic women, allowing them and their doctors to weigh the pros and cons of additional medical intervention to prevent neonatal hepatitis B infection.

Until there is a vaccine for hepatitis C, prevention will be mostly a matter of limiting exposure to the virus. People who inject drugs account for 75 percent of the roughly 30,500 new hepatitis C infections every year in the United States, so ending transmission depends on reaching this population. The best strategies to prevent hepatitis C combine both safer injection and treatment for the underlying addiction. Opioid agonist therapy uses prescription medicines - one example is methadone - to relieve the symptoms of drug withdrawal. Such treatment can prevent drug overdose and transmission of blood-borne infections, but 30 million Americans live in places where no providers prescribe these medicines. Syringe exchange programs are also essential, but they currently do not have sufficient reach, even in cities. Rural and suburban areas are home to about half of the people who inject drugs in United States, but these areas have only 30 percent of the nation's syringe exchange programs and distribute 8 percent of the total syringes. Syringe exchange programs do not encourage new drug users or increase drug use among clients, but laws in some states impede their functioning. The committee recommended expanded access to syringe exchange and opioid agonist therapy in accessible venues. Pharmacies, for example, may be a promising setting for syringe exchange, as they are easy to reach in most of the country and reasonably well equipped to provide a confidential space for counseling. Exchanges operating from a van or bus could also reach people in remote areas and may face less community opposition than a fixed-site exchange.

The direct-acting antiviral drugs that cure hepatitis C make elimination feasible in the United States, but their cost is an obstacle to large-scale treatment, creating inequities. While these drugs are very expensive, they are also cost-effective, when compared to other health care interventions. A recent study found that almost half of Medicaid patients were refused hepatitis C treatment, compared to only 5 percent of Medicare patients and about 10 percent of patients with commercial insurance. Furthermore, less than 1 percent of prisoners with hepatitis C have been treated. Faced with the unenviable task of allocating scarce treatment, some payers give first priority to the sickest patients - those at immediate risk of cirrhosis or end-stage liver disease. But delaying treatment increases a patient's risk of cirrhosis, liver cancer, and death. It also hurts society, as the untreated patient can still transmit the virus. Treating everyone with chronic hepatitis C, regardless of disease stage, would avert considerable suffering in hepatitis C patients and would pay off in a reduction in new infections.

Unrestricted, mass treatment of hepatitis C is necessary to eliminate the disease as a public health problem by 2030, but no direct-acting agent will come off patent before 2029. Delaying mass treatment until generic medicines are available would result in tens of thousands of deaths and billions of dollars in wasted medical costs. At the same time, innovator drug companies have the right to compensation for the risk they took to bring a valuable product to market, and society benefits from the financial incentive for pharmaceutical breakthroughs that patent protection offers. In an effort to balance these competing needs, the committee recommended that the government purchase a license or assignment to the patent on a direct-acting antiviral drug, and use it only in those market segments where the government pays for treatment and access is now limited, such as Medicaid and prisons. The committee proposed a voluntary transaction where six innovator pharmaceutical companies bid to sell a license to the government for use in a narrow market that the companies would not otherwise reach. This limitation will also control costs, because the government should not have to pay as much as if it were compromising the lucrative private market. The voluntary nature of this process guarantees the drug company reasonable compensation, and the patent holder has the option to walk away if the price is too low.

The committee's calculations suggested a patent license should cost about $2 billion, after which states and the federal government would pay about $140 million to produce the medicines needed to treat about 700,000 neglected patients. For comparison, under the status quo, it would cost about $10 billion over the next 12 years to treat only 240,000 of the same people.

Another challenge of eliminating hepatitis B and C in the U.S. is that people who have or are at risk for contracting the diseases often are not engaged in care and can be difficult to reach, including people who are born abroad, are uninsured, have substance use problems, and are or have been imprisoned. The committee recommended that the U.S. Department of Health and Human Services work with states to build a comprehensive system of care and support for such patients on the scale of the Ryan White system, which brought HIV services to millions of poor HIV patients.

Working through primary care providers can also improve the reach of hepatitis services. There is precedent for managing hepatitis C in primary care, but treating viral hepatitis carries risks that providers in small practices may be reluctant to accept, causing a disparity where viral hepatitis care is out of reach for people in rural and underserved communities. The committee recommended that the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America partner with primary care providers and their professional organizations to build capacity to treat hepatitis B and C in primary care.

People in jails and prisons bear a particularly high burden of viral hepatitis. The committee found an opportunity in this problem because correctional facilities are an ideal place to test and vaccinate for hepatitis B and to cure hepatitis C. Directly observed therapy is the norm and the risk of drug diversion is low. The committee recommended that the criminal justice system screen, vaccinate, and treat hepatitis B and C in correctional facilities according to national clinical practice guidelines.

The study was sponsored by the Centers for Disease Control and Prevention Division of Viral Hepatitis and Division of Cancer Prevention and Control; U.S. Department of Health and Human Services Office of Minority Health; American Association for the Study of Liver Diseases; Infectious Diseases Society of America; and National Viral Hepatitis Roundtable. The National Academies of Sciences, Engineering, and Medicine are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine. The National Academies operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln. For more information, visit http://national-academies.org. A roster follows.

AbstractBackground: There is a lack of evidence-based data on aged patients with newer direct-acting antivirals (DAAs) and with shorter duration of treatment regimens involving DAAs with or without ribavirin (RBV) and pegylated interferon (Peg IFN).Patients and methods: Medical records of 240 patients treated with DAAs with or without Peg IFN and RBV between January 2013 and July 2015 were retrospectively analyzed. Patients were divided into two groups: patients aged 65 years and older (N=84) and patients aged younger than 65 years (N=156). Pretreatment baseline patient characteristics, treatment efficacy, factors affecting sustained virologic response at 12 weeks after treatment, and adverse reactions were compared between the groups.

Results: No statistically significant difference was observed with end of treatment response (98.8 vs. 98%, P=0.667) and sustained virologic response at 12 weeks after treatment (93.1 vs. 94.1%, P=0.767) between patients aged 65 and older and those younger than 65 years of age. Fatigue was the most common adverse event recorded (32.5%), followed by anemia (19.6%), leukopenia (11.7%), thrombocytopenia (10%), skin rash (8.3%), and headache (7.9%). The RBV dose was reduced in eight (8%) patients and four patients discontinued the RBV treatment because of severe anemia. RBV dose reduction or discontinuation did not reach statistical significance (P=0.913). Increased fibrosis, cirrhosis, aspartate aminotransferase, alanine aminotransferase, hemoglobin, and platelet levels seem to affect the sustained virologic response in the elderly. Twelve (6.28%) patients failed to respond to treatment and the failure rate was not significant (P=0.767) between the groups.

Conclusion: DAAs with or without IFN and RBV in the standard recommended 12 or 24-week treatment regimens are effective, well tolerated, and may be safely extended to elderly patients infected with chronic hepatitis C.

Introduction
Globally, chronic hepatitis C virus (HCV) infection has been estimated to affect 2–3% (about 170 million) of the world’s population [1]. A National Health and Nutrition Examination Survey 2003–2010 analysis estimated that ∼2.7 (1.0%) million USA residents have infection with chronic HCV [2]. Chronic HCV is the leading cause of cirrhosis, hepatocellular carcinoma (HCC), and its related complications, and thus elimination of HCV signiﬁcantly reduces the risk of HCC, liver failure, and death [3].

An increased prevalence of chronic HCV infection is observed with advancing age. These patients are likely to have an advanced liver disease including cirrhosis of the liver and related complications [4,5]. In countries such as Japan, Taiwan, and some European countries, the prevalence of chronic hepatitis C infection is the highest in the aged population [6]. According to the USA Census Bureau, by 2030, more than 20% of USA residents are projected to be aged 65 years and older. The baby boomers (born between 1945 and 1965) began turning 65 in 2011 and currently account for three-fourth of all chronic HCV infections among adults in the USA [7].

Older individuals infected with chronic HCV are historically considered a difﬁcult to treat category with less success and more treatment failures than the younger population. The pegylated interferon (peg IFN) and ribavirin (RBV) combination therapy was associated with a high discontinuation rate in the elderly because of the longer duration of treatment and associated adverse events [8]. With the recent introduction of IFN-free direct-acting antivirals (DAAs), the treatment success for chronic HCV infection has improved markedly, with the overall cure rate reaching above 90%. Even though some of the newer drug trials included aged populations, the numbers of elderly patients enrolled were limited. Although we have achieved considerable advancements in treatment with newer agents, the coadministration of RBV in combination with newer agents still exists in certain patient groups to achieve an acceptable response rate. A shorter duration of treatment with these regimens and better tolerability are expected in both younger and older populations. We, therefore, examined the effectiveness and tolerability of newer DAAs in older patients aged older than 65 years compared with younger patients. We also evaluated the factors associated with sustained virologic response (SVR) and the tolerability of DAAs in combination with Peg IFN, RBV, or both with a shorter duration of treatment in an aged population compared with younger patients aged younger than 65 years.

Patients and methods
This retrospective cohort study protocol was approved by the institutional review board of each hospital (New York Presbyterian Brooklyn Methodist Hospital New York and Interfaith Medical Center, New York).

Patients
A total of 279 consecutive patients with chronic HCV treated with either a combination of DAAs or at least one of the newer agents in combination with IFN and RBV between January 2013 and July 2015 at two institutions were retrospectively analyzed. Thirty-nine patients were excluded from the study for various reasons including insufﬁcient documentation of viral load during the treatment and failure to attend follow-up after the end of treatment (Fig. 1). All the 240 patients included in this retrospective cohort study received at least eight weeks of treatment with one of the recommended combination regimens in standard doses for chronic HCV infection. Patients were divided into two groups: patients aged younger than 65 years (N=156) and those aged 65 years and older (N=84). The choice of treatment regimens used was made on the basis of the American Association of Study of Liver Disease guidelines during that period. During early 2013, treatment recommendation was triple therapy with a protease inhibitor, Peg IFN, and RBV. In the years 2014 and 2015, the rest of the regimens were used as they were approved one after the other by the Food and Drug Administration.

The duration of the treatment periodranged from a minimum of 8weeks(N=3, all with Harvoni) to a standard 12 weeks (N=201) or 24 weeks (N=36) depending on their status of previous treatment and cirrhosis. All patients who received the IFN-based regimen received PegIFN at a standard dose of 180mg subcutaneously once a week. A weight-based RBV dose was used at 1200mg daily in two divided doses for those weighing 75kg and 1000mg for those weighing less than 75kg.

Study assessments
Pretreatment baseline characteristics (Table 1), laboratory studies, baseline HCV viral load, treatment efﬁcacy with the end of treatment response (ETR), and sustained virologic response at 12 weeks after the completion of treatment (SVR12) were compared between the groups. We determined the factors associated with SVR on baseline characteristics by univariate analysis. A separate analysis was carried out in patients aged older than or equal to 65 years to determine the factors associated with SVR in the elderly group. The safety and tolerability of antiviral drug regimens were assessed by reviewing the documented common or serious adverse events, treatment completion rate, and reduction in the medication dosage or discontinuation of medications.

Assessment of liver ﬁbrosis was performed with invasive liver biopsy in some cases and noninvasive testing with a ﬁbrosure test or a ﬁbroscore test and the aspartate aminotransferase (AST)-to-aspartate platelet ratio index (APRI) score. Patients who had clinical, laboratory, and radiologic evidence of cirrhosis were treated without any further assessment of ﬁbrosis. Treatment response was assessed with HCV RNA viral load (IU/ml) at four weeks after initiation of treatment, at the end of treatment, and 12 weeks after the completion of treatment.

The test was performed using Cobas AmpliPrep/Cobas TaqMan HCV Quantitative Test, v2.0 (Roche Molecular Diagnostics, Pleasanton, California, USA) with a lower limit of quantiﬁcation of HCV RNA 15IU/ml. ETR was deﬁned as undetectable viral load at the end of completion of treatment. SVR12 was deﬁned as undetectable viral load at 12 weeks after the end of treatment.

Statistical analysis
The SPSS statistics software package (IBM SPSS Statistics, version 21; IBM Corp, Armonk, New York, USA) was used for statistical analysis. Values were expressed as mean±SD and the mean quantitative values were analyzed using Student’s t-test. The χ2-test was used to analyze differences in qualitative values. All P values were two tailed and a P value of less than 0.05 was considered signiﬁcant. One-way analysis of variance was used to determine whether there were differences among the group means. Univariate analysis was used to identify the factors related to SVR.

Results
Patients Sixty-ﬁve percent (N=156) of the total of 240 patients were younger than 65 years and patients aged 65 years or older comprised 35% (N=84) of treated patients, with the range being 22–94 years (59.96±10.89). Ninety-nine patients were men and 57 patients were women in the group younger than 65 years of age and 46 were men and 38 were women in the group 65 years of age and older, respectively. Most of the patients were Black (51%, 123/240), followed by White (23%, 56/240), Hispanic (11%, 27/240), and Asians (1%, 2/240). The 32 (13%) patients categorized as others were genotype (GT) 4 and were of Middle-Eastern or Egyptian origin. Also, 32 patients were coinfected with HIV and were receiving their antiretroviral therapy for HIV infection during HCV treatment; no dose adjustment was required. The basic clinical characteristics of all treated patients are summarized in Table 1.

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Table 1

GTs 1a and 1b was present in 78.3% of the treated patients. The next most common genotype was GT 4, found in 11.7% of patients. GTs 2 and 3 were present in 6.7 and 3.3% of all treated patients, respectively.

Seventy ﬁve patients were treatment experienced, 50 of whom were <65 years old and 25 patients who were ≥65 years. These treatment experienced patients had either previously failed treatment with the IFN and RBV combination or IFN and RBV in combination with newer DAAs. Model for end-stage liver disease (MELD) score was high in patients aged 65 years and older and was statistically signiﬁcant (P=0.048). A signiﬁcant difference was observed between the groups with baseline medical comorbidities HTN (P=0.004), coronary artery disease (P=0.041), and chronic kidney disease (P=0.008) in patients aged 65 years and older, and tended to have more comorbidities than younger age groups. Except for baseline hemoglobin (P=0.004) and alanine aminotransferase (ALT) (P=0.018), no difference was noted between the initial laboratory studies within the groups. The mean viral load remained similar in both groups (P=0.624). No statistical signiﬁcance was observed with sex (P=0.189), BMI (P=0.713), APRI score (P=0.619), or status of previous treatment (P=0.715).

Response to therapy
In seven out of the total 240 patients, no end of treatment response was recorded; however, viral load was recorded as undetectable at 4 or 8 weeks on treatment, except one patient, who had a quantiﬁable viral load at 2 weeks. SVR12 was not reported in 49 patients, either because of pending follow-up or because it was not determined and recorded. With all the treatment regimens combined, the overall ETR rate was 98.2% (N=233) and SVR12 was 94% (N=191) (Figs 3 and 4).

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Figs 3 and 4

No statistically signiﬁcant difference was observed with ETR (98.8 vs. 98%, P=0.667) and SVR12 (93.1 vs. 94.1%, P=0.767) between patients aged 65 years and older and those younger than 65 years of age. SVR12 for DAA with IFN and RBV treatment was 98% (49/50), higher than 91.4% (118/129) achieved with IFN-free DAA regimens, but was not statistically signiﬁcant. A similar response rate was observed in patients older than or equal to 65 years, with 100% of the patients on the IFN-based regimen achieving an SVR compared with only 91.07% SVR with the IFNfree treatment regimen. ETR and SVR12 for GTs 1a, 1b, 2, 3, and GT 4 were 97.7, 100, 93.8, 100, and 100% and 92, 100, 92.9, 83.3, and 91.7%, respectively (Fig. 6).

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Fig. 6

Patients with GT 3 were the lowest responders, highlighting the fact that GT 3 is the most difﬁcult to treat with DAA agents. The ETR rate and SVR12 rates for subgroups Peg IFN+RBV+SOF, SOF+RBV, Harvoni, Viekira Pak/ Viekira Pak+RBV, and SPV+SOF were 100, 96.7, 97.4, 100, 98.1%, and 97.8, 88, 94.1, 100, and 90.6%, respectively.

For patients who had previous treatment failure or were naïve to treatment, no signiﬁcant difference in ETR (P=0.783) or SVR12 (P=0.947) was observed between the younger and the older age groups. The univariate analysis determined the factors associated with an SVR (Table 2). The SVR12 was signiﬁcantly lower in patients with high APRI and a high MELD score, indicating that advanced ﬁbrosis is a major factor in determining the response to treatment (P=0.001 and 0.008, respectively). Baseline ALT and AST were signiﬁcantly higher in patients who failed to achieve an SVR than in patients who did achieve SVR12 (P=0.016 and 0.000, respectively). BMI was signiﬁcantly higher in patients who achieved SVR12 (P=0.000) Table 2. Factors associated with SVR12 were analyzed separately for patients aged older than or equal to 65 years (Table 4).

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Table 4

The ratio of GT 1 patients who achieved an SVR12 was signiﬁcantly lower compare to other genotypes (P=0.001). Cirrhosis and MELD score of more than ten were associated with a low SVR (P=0.001 and 0.042, respectively). Baseline ALT and AST tended to be higher in those who did not achieve an SVR (P=0.020 and 0.000, respectively) and BMI tended to be lower in patients who failed to respond to treatment. Only seven patients had the IL28B GT tested and hence were not included in the evaluation of factors predicting the SVR. There were 12(6.28%) patients(5≥65and7<65years) who failed to respond to treatment. Eight patients developed relapse after treatment, three responded partially, and one achieved a virologic breakthrough during the treatment period (Table 3). Nine out of 12 patients who did not respond to treatment were cirrhotic. The difference in the failure rate between the two groups was not signiﬁcant statistically (P=0.767).

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Table 3

Safety and tolerability
None of the adverse reactions reported were severe, except severe anemia in two patients. Fatigue was the most common adverse event recorded (32.5%), followed by 65 years) patients discontinued the RBV treatment because of severe anemia (decrease in hematocrit >25% from baseline); however, they all achieved SVR12. RBV dose reduction or discontinuation did not reach statistical signiﬁcance between the two groups (P=0.913) (Fig. 5).

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Fig. 5

Discussion
Eradication of HCV reduces the risk of progression to cirrhosis, HCC, and liver-related mortality, and thus leads to an improvement in overall survival and quality of life [9]. Historically, the standard longer duration of IFN and RBV treatment produced signiﬁcant adverse events in elderly patients, necessitating dose reduction or discontinuation of medications [10,11]. The overall SVR rate was less than 50% with standard dual therapy with Peg IFN and RBV regimens. With the introduction of ﬁrst DAAs in 2011, the triple therapy (boceprevir or telaprevir with Peg IFN and RBV) increased the SVR12 to 65–70% in GT 1 patients. Subsequent, substantial progress with further trials including combination NS5A and NS5B inhibitors, SVR12 approached more than 90%. Current guidelines do not specify the age limit for treating elderly patients.

The American Association of Study of Liver Disease recommends one of the six- DAA combination regimens for GT 1, the most common type of chronic HCV infection in the United States [12]. RBV is still an integral part of the treatment regimen and utilized in combination with DAAs in GT 4 and as an alternative treatment regimen in GTs 1 and 3 patients with compensated cirrhosis.

A recent meta-analysis by Yang et al. [8] concluded that the overall SVR in patients aged older than or equal to 65 years treated with a prolonged course of IFN/RBV regimens was signiﬁcantly lower and had a signiﬁcantly higher risk of relapse than in patients younger than 65 years of age. IFN and RBV discontinuation rate were also signiﬁcantly higher in older patients than in younger patients.

We did not ﬁnd any signiﬁcant difference in RBV dose reduction or discontinuation rate (P=0.913) in patients aged 65 years and older compared with younger patients. These ﬁndings indicate that elderly patients are tolerating equally the shorter course of treatment involving better tolerated and can be administered to any age group safely with close monitoring during the treatment.

In most initial trials on protease inhibitors, a small number of patients older than 65 years of age were included. Although there was no upper age limit in NS5B nucleotide polymerase inhibitor SOF and NS3/4A second generation protease inhibitor simeprevir trials, the number of elderly patients included was too small to draw any conclusion [14,15]. In most of the trials involving SOF, most of the patients treated were in their 50s [16–21]. In our study, 54 (27 in each group) patients treated with SPV and the SOF regimen showed similar SVR12 rates (P=0.607) and adverse events proﬁle. Overall, SVR12 treated with an SOF-based regimen was 91–98%, in agreement with the results observed from the major trials involving SOF [18–22]. In trials involving Viekira Pak, the study group involved were younger than 71 years, with a mean age in the 50s, and the SVR rate was well above 88% [22–26]. Overall, the response rate with Viekira Pak in our study was 100% (12<65 and 6> 65 years), with good tolerance to medication in elderly patients. Clinical trials involving IFN and RBV-free regimens also did not include enough patients aged 65 years and older to determine whether they respond differently from a younger population.

Trials involving the NS5A inhibitor LDV and SOF in ION1, 2, and 3 trials included only 117 patients aged65yearsandolder,andthepatientpopulationincluded in Lone Star Study involving the LDV and the SOF combination was younger than 70 years [27–30]. No overall difference in tolerability and effectiveness was observed with elderly patients, but the data available for the treatment of the aged population with newly approved therapies are still limited not only in registration trials but also in real-world treatments and community-based HCV regimens. Results of evaluation of 80 (52<65 and 28> 65 years) patients treated with Harvoni in our study yielded an ETR of 97% and an SVR12 of 94%, consistent with the results observed in clinical trials. No statistically signiﬁcant difference was noted in our study with ETR (P=0.209) or SVR12 (P=0.120) between the two age groups, consistent with the recently published study by Saab et al. [31]. They analyzed the data from four open-label phase 3 clinical trials that evaluated the safety and efﬁcacy of LDV+SOF and concluded that the combination of LDV and SOF is safe, effective,andwelltoleratedinpatientsolderthan65yearsof age who have GT 1 hepatitis C infection [31]. Of the 2293 patients enrolled in four phase 3 trials, 264 (12%) were older than or equal to 65 years of age, of whom 24 were aged older than or equal to 75 years. 97% of patients aged younger than 65 years achieved SVR12 (1965/2029) and 98% (258/264) of patients aged older than or equal to 65 years achieved SVR12. The most common adverse events in both age groups that occurred in 10% or more patients were headache and fatigue.

Most adverse events noted in our study were minor and did not require any intervention, comparable with the study reports from major trials involving similar treatment regimens (Table 5). Adverse events did not differ signiﬁcantly between the groups, except abdominal pain (P=0.018). Ten (6.4%) patients, all younger than 65 years of age, complained of nonspeciﬁc abdominal pain on treatment. Considering that the population involved had signiﬁcant pain issues at baseline, it appears that this symptom may not be entirely related to the medication agent used. There were two serious adverse reactions during treatment with the regimen involving RBV with severe anemia requiring a blood transfusion and two patients received darbepoietin infusion for correction of anemia. None of the patients discontinued the complete treatment regimen in our study because of adverse reactions, although four patients discontinued the RBV during the treatment; they all achieved SVR12. In 12% of the patients, the RBV dose was reduced during treatment.

A recent study by Pernas [32] raised a concern about possible drug interactions and RBV dose reduction because of adverse reactions in a signiﬁcant number of patients after following 125 patients 65 years and older who were treated for hepatitis C with newer DAA agents. Of the 61.2% of patients who received RBV, in almost half, the dose was reduced during treatment [32].

Clinical trials involving a recently approved IFN-free regimen for GTs 1 and 4, elbasvir, and grazoprevir (Zepatier; Merck & Co Inc, Kenilworth, New Jersey, USA) with or without RBV included 187 patients aged 65 years or older [33]. The higher rate of late ALT elevation was observed in elderly patients; however, no dosage adjustment was required and the ALT level of most patients normalized after the completion of treatment. SVR differs with GTs. We found a statistically signiﬁcant low SVR rate with GT 1 in an elderly age group. There are no data identifying which patients will achieve an SVR among older patients with a DDA-based treatment. Our analysis indicates that cirrhosis and increased MELD score are important factors for low SVR in general and in elderly patients. Univariate analysis showed that baseline BMI, ALT, AST, and hemoglobin are factors that are associated signiﬁcantly with an SVR (P=0.020, 0.020, 0.000, and 0.013, respectively). In our study, 12 (6.28%) patients failed to respond to treatment (7<65 and 5≥65 years). Age was not a factor for the poor virologic response and the failure rate between the groups was not signiﬁcant (P=0.767). All patients reported adherence to the medication regimen, and there was no clinical evidence of any reinfection in relapsed patients.

None of these patients had any pretreatment-resistant or post-treatment-resistant associated variants and are awaiting further treatment. Seventy-ﬁve (nine out of 12) percent of the patients who failed to respond to treatment were cirrhotic and 41% (ﬁve out of 12) were coinfected with HIV. Further studies are required to evaluate these signiﬁcant numbers of relapses in HIV-coinfected patients. Nine patients who failed to treatment received one or the other SOF-based regimen.

Some of the limitations of this study are the retrospective nature of our study, the fact that documentation of the common adverse events may not be complete, and that elderly patients involved are still a small number compared with registration trials.

However, to our knowledge, our study is the ﬁrst study involving a real-world community-based treatment comparing HCV patients younger than 65 years of age and 65 years of age and older. Going forward, the IFN-free regimens seem to be the standard of care in both age groups. RBV in combination with other DAAs may still be useful in treating some of the difﬁcult to treat patient groups and in less developed countries, where the cost of newer antiviral medicines is a major hurdle. Shortened treatment course may reduce the drug-related adverse events in general including elderly patients. There is a pressing need to include older patients in future trials involving IFN-free agents. They require more complex decision-making because of their age and comorbid conditions with multiple medications.

Conclusion
The age of the patient does not seem to have a major impact on the virologic response rate when treating chronic HCV infection. Older patients (age 65 years and older) do not appear to have a higher frequency of adverse events compared with younger patients. Increased ﬁbrosis, cirrhosis, some of the baseline laboratory studies including AST, ALT, Hemoglobin, and platelet levels seem to affect the SVR in the elderly and require further studies. More studies should be carried out in an older population of patients to assess the safety, efﬁcacy, and adverse reactions of newer DAAs regimens. Treatment should not be withheld purely on the grounds of advanced age.

Abstract
Objectives
Twenty-eight states in the U.S have legalized medical marijuana, yet its impacts on severe health consequences such as hospitalizations remain unknown. Meanwhile, the prevalence of opioid pain reliever (OPR) use and outcomes has increased dramatically. Recent studies suggested unintended impacts of legalizing medical marijuana on OPR, but the evidence is still limited. This study examined the associations between state medical marijuana policies and hospitalizations related to marijuana and OPR.

Methods
State-level annual administrative records of hospital discharges during 1997–2014 were obtained from the State Inpatient Databases (SID). The outcome variables were rates of hospitalizations involving marijuana dependence or abuse, opioid dependence or abuse, and OPR overdose in 1000 discharges. Linear time-series regressions were used to assess the associations of implementing medical marijuana policies to hospitalizations, controlling for other marijuana- and OPR-related policies, socioeconomic factors, and state and year fixed effects.

Results
Hospitalizations related to marijuana and OPR increased sharply by 300% on average in all states. Medical marijuana legalization was associated with 23% (p = 0.008) and 13% (p = 0.025) reductions in hospitalizations related to opioid dependence or abuse and OPR overdose, respectively; lagged effects were observed after policy implementation. The operation of medical marijuana dispensaries had no independent impacts on OPR-related hospitalizations. Medical marijuana polices had no associations with marijuana-related hospitalizations.

Conclusion
Medical marijuana policies were significantly associated with reduced OPR-related hospitalizations but had no associations with marijuana-related hospitalizations. Given the epidemic of problematic use of OPR, future investigation is needed to explore the causal pathways of these findings.

Media Coverage Of This ArticleWould legalizing medical marijuana help curb the opioid epidemic?
By Ronnie Cohen

(Reuters Health) - In states that legalized medical marijuana, U.S. hospitals failed to see a predicted influx of pot smokers, but in an unexpected twist, they treated far fewer opioid users, a new study shows.

Hospitalization rates for opioid painkiller dependence and abuse dropped on average 23 percent in states after marijuana was permitted for medicinal purposes, the analysis found. Hospitalization rates for opioid overdoses dropped 13 percent on average.

At the same time, fears that legalization of medical marijuana would lead to an uptick in cannabis-related hospitalizations proved unfounded, according to the report in Drug and Alcohol Dependence.

March, 19, 2017
MD WhistleblowerMedical Marijuana Use - Ready, Fire, Aim!
Michael Kirsch, MD
Promoting medical marijuana use is hot – smokin’ hot. States are racing to legalize this product, both for recreational and medical use. In my view, there’s a stronger case to be made for the former than the latter. Continue reading...

BURLINGTON, Mass.--(BUSINESS WIRE)--
March 27, 2017
ArQule, Inc. (ARQL) today reported that its partner, Kyowa Hakko Kirin, announced top-line results of the JET-HCC Phase 3 trial of tivantinib in Japan, and that the trial did not meet its primary endpoint of progression free survival (PFS).

JET-HCC is a randomized, double-blind placebo-controlled study that enrolled approximately 190 Japanese patients with c-Met diagnostic-high inoperable hepatocellular carcinoma (HCC) with a history of prior sorafenib therapy, to evaluate the efficacy and safety of tivantinib.

The primary endpoint of the trial is PFS, and the top-line results did not show a significant difference in PFS between the tivantinib group and the placebo group. There were no new safety issues observed in the trial.

The details of the study results will be presented in an upcoming scientific forum.

“I would like to thank our partner, Kyowa Hakko Kirin, and all the participants in their study,” said Paolo Pucci, Chief Executive Officer of ArQule. “The results are disappointing as there is a need for a second-line HCC therapy in Japan.”

HCV Education
Review learning activities, editorials, with new data about interferon-free regimens approved for HCV, as well as investigational drugs still in the pipeline. Links are provided to support, patient friendly information, clinical trials, peer-reviewed journals, videos, conferences with commentary, all updated on a continuous basis.

Users can search for a hepatitis C clinical trial by category (genotype), or learn how to evaluate a clinical trial and become familiar with commonly used terms. HCV Advocate offers an easy to navigate HCV Medications Blog as well, organized by HCV genotype

View each rebuttal and all ongoing media coverage. In June the HCV community was blindsided when an article with a somewhat "clickbait" headline was released by The Guardian. The Guardian reported on a systematic review published by the Cochrane Collaboration that suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits.

The controversy over expensive new drugs for hepatitis C
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions/India, Egypt and other lower-income countries or through online "buyers clubs"

Liver Cancer After Treatment For Hepatitis C
​Research demonstrates that while SVR markedly reduced liver-related complications and liver cancer, some long-term risk for liver cancer remained in those who were cured of Hepatitis C. But after direct-acting antiviral therapy does the risk of developing liver cancer increase?

Meeting Updates

April 19-23
The European Association for the Study of the Liver (EASL) International Liver Congress (ILC 2017)

Merck today announced its strategic decision to discontinue the development of the investigational combination regimens MK-3682B (grazoprevir/ruzasvir/ uprifosbuvir) and MK-3682C (ruzasvir/uprifosbuvir) for the treatment of chronic hepatitis C virus (HCV) infection. This decision was made based on a review of available Phase 2 efficacy data and in consideration of the evolving marketplace and the growing number of treatment options available for patients with chronic HCV infection

Two HCV Drugs to Be Discontinued
The Food and Drug Administration (FDA) announced that Rebetol(ribavirin; Merck) capsules and PegIntron (peginterferon alfa-2b; Merck) for Injection are being discontinued. The decision is business-related and not due to safety or efficacy issues with the drugs.

Rebetol is a nucleoside analogue indicated for chronic hepatitis C in combination with interferon alfa-2b (pegylated and nonpegylated), in patients ≥3 years of age with compensated liver disease. It is supplied as 200mg capsules in 56-, 70-, and 84-count bottles. The Rebetol discontinuation is effective February 1, 2016.
PegIntron is an antiviral indicated for treatment of chronic hepatitis C in patients with compensated liver disease. It is supplied as 50mcg/0.5mL, 80mcg/0.5mL, 120mcg/0.5mL, and 150mcg/0.5mL single-use vials and single-use pre-filled pens. No effective date is available for the PegIntron discontinuation.

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